Frequency and Nature of Albumin/Globulin Misinterpretation in Laboratory Testing
Albumin and globulin levels are frequently misinterpreted in clinical practice, particularly due to methodological limitations of common laboratory assays and failure to account for disease-specific protein alterations—the bromocresol green (BCG) method overestimates albumin by approximately 0.4-0.6 g/dL in nephrotic syndrome and other hypoalbuminemic states, leading to systematic errors in clinical decision-making. 1, 2
Primary Sources of Laboratory Misinterpretation
Assay-Specific Measurement Errors
The BCG colorimetric method, used by most clinical laboratories, overestimates serum albumin by a mean of approximately 0.61 g/dL overall, with particular overestimation below the normal range. 1
In nephrotic syndrome specifically, BCG method yields albumin values that are higher by an average of 0.4 g/dL compared to the gold-standard cellulose acetate electrophoresis method. 2
This overestimation occurs because BCG reacts with α2-globulin and other proteins in addition to albumin, causing interference that is directly proportional to elevated α2-globulin levels commonly seen in nephrotic patients. 2
The bromocresol purple (BCP) method has opposite problems—it underestimates serum albumin by approximately 0.71 g/dL in hemodialysis patients and by 19% compared to nephelometry in chronic kidney disease patients. 1
Clinical Context-Dependent Misinterpretation
Albumin levels must be interpreted cautiously as isolated values do not necessarily predict nutritional status and must be followed over time in context of peritoneal membrane transport type, total solute clearance, volume status, chronic liver disease, comorbidities, and inflammatory states. 1
In nephrotic syndrome, the threshold for venous thromboembolism risk is serum albumin below 2.9 g/dL, but this threshold varies depending on whether the laboratory uses BCG (which overestimates) or BCP (which underestimates) assay methods. 1
Physicians must know which assay and normal range their local laboratory reports, as BCG overestimates albumin in nephrotic syndrome, potentially leading to underestimation of thrombotic risk. 1
Disease-Specific Misinterpretation Patterns
Nephrotic Syndrome
In nephrotic syndrome, albumin is reduced while α2-globulin and total cholesterol are significantly increased, creating a protein pattern that interferes with BCG measurement accuracy. 2
The liver increases unselective synthesis of all protein types to compensate for urinary losses, meaning globulins may rise even as albumin falls—this compensatory response is missed when focusing solely on albumin values. 3
Fructosamine assays, sometimes used as alternatives to albumin for monitoring, are not useful in nephrotic syndrome because they are influenced by both hypoalbuminemia and altered immunoglobulin levels. 4
Liver Disease
In cirrhosis, albumin decreases while globulins typically rise, but very low aminotransferases with low albumin may suggest chronic stable disease without active inflammation rather than acute hepatocellular injury. 5
Albumin concentrations are reduced in many non-hepatic conditions including sepsis, systemic inflammatory disorders, nephrotic syndrome, malabsorption, and gastrointestinal protein loss—overinterpretation of low albumin as indicating liver disease severity is a common pitfall. 5
The globulin compensation index (GCI) shows that globulin rise with reduced albumin occurs in 72.3% of hepatic diseases but only 32.3% of non-hepatic systemic diseases, yet this distinction is rarely made in routine practice. 6
Chronic Kidney Disease and Dialysis
In end-stage kidney disease, HbA1c can be falsely low due to anemia, erythropoietin use, reduced erythrocyte lifespan, and blood transfusions, while fructosamine is inaccurate due to hypoalbuminemia. 1
Glycated albumin has been proposed as a better indicator but is also impacted by low albumin levels, limiting its utility despite being less affected by confounding factors than HbA1c. 1
Critical Clinical Pitfalls
Threshold Misapplication
The definition of nephrotic syndrome in children should maintain serum albumin ≤2.5 g/dL rather than the suggested <3 g/dL cutoff, as there is no evidence that children with albumin 2.6-2.9 g/dL have similar pathology or treatment responses. 1
For peritoneal dialysis adequacy, the normal range for BCG method is 3.8-5.1 g/dL, differing from electrophoretic method by approximately 0.3 g/dL—using wrong reference ranges leads to inappropriate clinical decisions. 1
Albumin/Globulin Ratio Misinterpretation
An elevated albumin/globulin ratio (e.g., 2.7) suggests relative globulin deficiency and may indicate protein-losing conditions causing secondary immunodeficiencies, yet this pattern is frequently overlooked. 7
Discordant results such as elevated total protein with normal or low albumin should prompt investigation for paraproteinemias, but confusion with inflammatory states (where albumin decreases while globulins increase) is common. 8
Dehydration vs. Disease States
Dehydration or hemoconcentration is the most common cause of simultaneously elevated total protein and albumin, yet clinicians often pursue extensive workup before considering this simple explanation. 8
In HIV infection, high total protein typically occurs with normal or low albumin due to B-cell hyperplasia and increased immunoglobulins—if both are elevated, dehydration remains most likely rather than disease progression. 8
Recommended Approach to Minimize Misinterpretation
Laboratory Method Verification
Request BCG method if available, as it has proved more clinically reliable than BCP despite its limitations, with low coefficient of variation (5.9%) and lack of interference from lipemia, salicylates, or bilirubin. 1
If BCP method must be used, apply less clinical weight to serum albumin concentrations and rely more heavily on other markers of malnutrition or disease severity in end-stage renal disease patients. 1
Know your laboratory's specific assay method and normal range—this information should be verified for every patient when making critical decisions about thromboprophylaxis, nutritional status, or disease severity. 1
Comprehensive Protein Assessment
Evaluate complete blood count to assess for hematological abnormalities associated with immune deficiency and signs of infection or inflammation when globulin abnormalities are detected. 7
Calculate prothrombin time and INR to assess clotting factor synthesis, obtain complete metabolic panel, urinalysis, and platelet count when low albumin is found with liver lesions or suspected synthetic dysfunction. 5
Consider protein electrophoresis when total protein is elevated with normal or low albumin, or when albumin/globulin ratio is abnormal, to identify paraproteinemias or specific globulin fraction abnormalities. 8